#118 – Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging

A prominent scientist in the field of mTOR research, credited with identifying mTOR in mammals and elucidating its two different complexes (TORC1 and TORC2).

Another leading researcher in the field of aging and Rapamycin, mentioned for his work on Rapamycin in dogs.

Host of The Drive podcast and interviewee.

Colleague of Lloyd Klickstein who facilitated the introduction for the podcast, and recruited Klickstein to lead the musculoskeletal department at Novartis Institutes.

Scientist recognized for her pioneering work on CRISPR technology.

Guest of the podcast, Chief Scientific Officer at Restore Bio, previously at Novartis and Brigham and Women's Hospital. Senior author on a pivotal 2014 paper on Rapamycin.

Lead author on the December 2014 paper that was pivotal in the speaker's understanding of Rapamycin for longevity, and later became a champion of the Restore Bio program.

Founder of the Novartis Institutes, credited with challenging Lloyd Klickstein and others to explore new areas of drug development, including the biology of aging.

Russian scientist and embryologist who did pioneering work on phagocytes and cellular immunity in the late 1800s.

Researcher who leads the TAME study, aiming to evaluate the benefits of Metformin in non-diabetics for aging-related diseases.

German scientist who, along with others, worked on humoral immunity (antibodies) at the same time Ilya Mechnikov was researching cellular immunity.

Author of a recent paper from David Sabatini's lab, which explored selective mTORC1 inhibition and how rapamycin analogs bind to different immunophilins.

Author of a paper on unpaired hemoglobins in thalassemia patients, providing a new clinical paradigm for testing drugs that augment autophagy.

Researcher whose work on fasting in mice (e.g., prior to femoral artery ligation) demonstrated significant survival benefits.

Targeting Aging with Metformin, a study led by Nir Barzilai to investigate if Metformin can prevent or delay age-related diseases in non-diabetic individuals.

The institution where Lloyd Klickstein received his MD PhD and was an academic physician, also a 'primitive academic environment' according to Klickstein due to funding models for physician-scientists.

The code name for Everolimus in the 2014 paper, a rapalog tested in patients for its impact on immune function.

Another rapalog, mentioned as a different molecule than Rapamune or Everolimus.

A phosphodiesterase-5 (PDE5) inhibitor drug used as an example to explain drug exposure, half-life, peak and trough levels.

An aminoglycoside antibiotic used as an example of a drug that produces toxicity by its trough levels, requiring drug-free time for organ recovery.

A compound originally identified on Easter Island and a key focus of the discussion, known for its ability to inhibit mTOR and its potential longevity effects, distinct from its immunosuppressive uses.

Another PDE5 inhibitor, mentioned in contrast to Cialis for its shorter half-life.

Also known as avarolamus, a rapamycin analog (rapalog) which was the specific drug used in the 2014 Manick/Klickstein study (referred to as rad001).

The specific drug by Pfizer (originally Wyeth) that was FDA approved in 1999 for transplantation, often used by the host in residency.

A drug with interesting antidepressant properties, specifically for recalcitrant depression, and speculated to activate mTOR.

A drug that is excellent for diabetics and has shown retrospective data of longevity in treated diabetics, but its benefit in perfectly healthy individuals is questioned due to its potential adverse effects on mitochondrial function.

The institution where Lloyd Klickstein received his bachelor's degree.

The Centers for Disease Control and Prevention, whose surveillance experiments indicate rhinovirus is the most common cause of respiratory tract infections.

A flagship program at Harvard where Lloyd Klickstein was an academic physician, and also worked in a laboratory earlier in his career.

The newspaper that sent an embargoed copy of the 2014 paper to the host, highlighting its significance.

A biotech company that uses an mTOR activator to treat depression, and is known by Lloyd Klickstein.

A clinical-stage biopharmaceutical company focused on developing medicines that target mTOR inhibition. Lloyd Klickstein is their Chief Scientific Officer.

A major pharmaceutical company where Lloyd Klickstein previously served as Global Head of Translational Medicine for the new indication discovery unit.

Mechanistic Target of Rapamycin, a master integrator of nutrient and growth factor availability that regulates cell growth, protein synthesis, lipid synthesis, and resource conservation.

One of the compounds in a cocktail studied for its effect on the epigenetic clock, noted for its ability to enlarge the thymus and its biological activity driven by IGF-1.

A substance in the blood that upregulates many proteins involved in preventing viral infections, activated by mTOR inhibition to decrease respiratory tract infections.

Clustered Regularly Interspersed Short Palindromic Repeats, a Nobel Prize-winning technology for gene editing, used as an example of basic science with unexpected practical applications.

A biological clock that estimates age by looking at methylation patterns on peripheral blood leukocyte DNA. Used in a recent study that claimed to set back the clock with a cocktail of drugs.

A specific example of a non-transplant/non-malignant disease where rapalogs like RAD001 were tested, showing biochemical changes in patients' blood.

Dehydroepiandrosterone, a hormone that substantially decreases with age but whose replacement has shown no clinical benefit in studies, used in a cocktail to reduce hyperinsulinemia from growth hormone.